title: Impact of fatty acids on human UDP-glucuronosyltransferase 1A1 activity and its expression in neonatal hyperbilirubinemia.
abstract: While breast milk has been known as a cause of neonatal hyperbilirubinemia, the underlying mechanism of breast milk-induced jaundice has not been clarified. Here, the impact of fatty acids on human UDP-glucuronosyltransferase (UGT) 1A1--the sole enzyme that can metabolize bilirubin--were examined. Oleic acid, linoleic acid, and docosahexaenoic acid (DHA) strongly inhibited UGT1A1 activity. Forty-eight hours after a treatment with a lower concentration of DHA (10 mg/kg), total bilirubin significantly increased in neonatal hUGT1 mice, which are human neonatal jaundice models. In contrast, treatments with higher concentrations of fatty acids (0.1-10 g/kg) resulted in a decrease in serum bilirubin in hUGT1 mice. It was further demonstrated that the treatment with higher concentrations of fatty acids induced UGT1A1, possibly by activation of peroxisome proliferator-activated receptors. Our data indicates that activation of peroxisome proliferator-activated receptors would increase UGT1A1 expression, resulting in reduction of serum bilirubin levels in human infants.
authors.affiliation: School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, JAPAN.
authors.forename: Ayako
authors.initials: A
authors.lastname: Shibuya
authors.forename: Tomoo
authors.initials: T
authors.lastname: Itoh
authors.forename: Robert H
authors.initials: RH
authors.lastname: Tukey
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Fujiwara
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001663:Bilirubin / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051556:Hyperbilirubinemia, Neonatal / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D007567:Jaundice, Neonatal / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D008041:Linoleic Acids / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009829:Oleic Acids / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000099148:UGT1A1 Enzyme
chemical_list: D001663:Bilirubin; D004281:Docosahexaenoic Acids; D014453:Glucuronosyltransferase; D008041:Linoleic Acids; D009829:Oleic Acids; D012333:RNA, Messenger; D000099148:UGT1A1 Enzyme